PTP61F Mediates Cell Competition and Mitigates Tumorigenesis.

John E. La Marca,Lee F. Willoughby,Kirsten Allan,Pei Kee Goh,Marta Portela,Tony Tiganis,Helena E. Richardson

doi:10.3390/ijms222312732

Abstract

Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a model organism, we have defined a role for protein tyrosine phosphatase 61F (PTP61F) (orthologue of mammalian PTP1B and TCPTP) in the initiation and progression of epithelial cancers. We demonstrate that a Ptp61F null mutation confers cells with a competitive advantage relative to neighbouring wild-type cells, while elevating PTP61F levels has the opposite effect. Furthermore, we show that knockdown of Ptp61F affects the survival of clones with impaired cell polarity, and that this occurs through regulation of the JAK–STAT signalling pathway. Importantly, PTP61F plays a robust non-cell-autonomous role in influencing the elimination of adjacent polarity-impaired mutant cells. Moreover, in a neoplastic RAS-driven polarity-impaired tumor model, we show that PTP61F levels determine the aggressiveness of tumors, with Ptp61F knockdown or overexpression, respectively, increasing or reducing tumor size. These effects correlate with the regulation of the RAS–MAPK and JAK–STAT signalling by PTP61F. Thus, PTP61F acts as a tumor suppressor that can function in an autonomous and non-cell-autonomous manner to ensure cellular fitness and attenuate tumorigenesis.

Highlights

Over the past century, Drosophila melanogaster has proven a suitable organism for modelling a range of human disorders, including cancer
We have examined a role for protein tyrosine phosphatase 61F (PTP61F), the Drosophila orthologue of the mammalian protein tyrosine phosphatases (PTPs) PTP1B and TCPTP, in pre-tumorigenic and tumorigenic tissue models
We observed that the loss of protein tyrosine phosphatase 61F (Ptp61F) allows otherwise wild-type clones to outcompete their wild-type neighbours, and Ptp61F knockdown allows polarity-impaired “loser” cell clones to overcome some of their relative fitness disadvantage

Summary

Introduction

Drosophila melanogaster has proven a suitable organism for modelling a range of human disorders, including cancer. (DLG1) (human orthologues SCRIB and DLG1-4, respectively) (reviewed in [4]) Together, these alterations promote the formation of neoplastic, invasive tumors in developing. The core concept of cell competition is that cells within a tissue are intrinsically competing with one another—that is, the fitness of each cell is surveyed relative to their neighbouring cells, and cells that are less fit are actively eliminated to maintain tissue homeostasis (reviewed in [16]). This is a conserved mechanism, though it is not so well studied in mammals as it is in flies (reviewed in [17]). The roles and targets of each cell competition-induced signalling pathway and the interplay between them are not completely understood, but many are regulated via the actions of protein tyrosine kinase (PTK) pathways, making the investigation of protein tyrosine phosphatases (PTPs) that regulate these pathways in cell competition a logical step

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